Depends on how good a shot you are.
I read a study were a .22 can be a very effective defense weapon, especially for women and girly men.
With a large cal handgun your first shot is fairly accurate. Successive shots tend to be off target due to the anticipation of the recoil. The likelyhood of you getting more hits in the kill zone is increased with a lighter gun.
I think it's best to be prepared but pray you never have to use a gun.